Abstract
Colorectal cancer (CRC) is a highly aggressive cancer in which metastasis plays a key role. However, the mechanisms underlying metastasis have not been fully elucidated. Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a regulator of mitochondrial function, has been reported as a complicated factor in cancer. In this study, we found that PGC-1α was highly expressed in CRC tissues and was positively correlated with lymph node and liver metastasis. Subsequently, PGC-1α knockdown was shown to inhibit CRC growth and metastasis in both in vitro and in vivo studies. Transcriptomic analysis revealed that PGC-1α regulated ATP-binding cassette transporter 1 (ABCA1) mediated cholesterol efflux. Mechanistically, PGC-1α interacted with YY1 to promote ABCA1 transcription, resulting in cholesterol efflux, which subsequently promoted CRC metastasis through epithelial-to-mesenchymal transition (EMT). In addition, the study identified the natural compound isoliquiritigenin (ISL) as an inhibitor that targeted ABCA1 and significantly reduced CRC metastasis induced by PGC-1α. Overall, this study sheds light on how PGC-1α promotes CRC metastasis by regulating ABCA1-mediated cholesterol efflux, providing a basis for further research to inhibit CRC metastasis.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81572972), the Supporting Plan of Scientific and Technological Innovation Team in Universities of Henan Province (20IRTSTHN029), the Scientific and Technological Research Project of Henan Province (212102310250).
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WC, QSZ and JL contributed to the design of the experiments. WC, QSZ, XSD, YHC, KZ and XXD performed the experiments and analyzed the data. XHC, CJZ and RHB helped to perform the experiments and contributed to the software analysis. YQ, JMZ, FT, KDL and ZMD helped to perform material preparation and data analysis. WC and QSZ wrote the manuscript. JL revised the manuscript and supervised the study.
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Chen, W., Zhang, Q., Dai, X. et al. PGC-1α promotes colorectal carcinoma metastasis through regulating ABCA1 transcription. Oncogene 42, 2456–2470 (2023). https://doi.org/10.1038/s41388-023-02762-y
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DOI: https://doi.org/10.1038/s41388-023-02762-y
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